Endocrine-disrupting chemicals (EDCs) are present throughout the environment, from wastewater effluent to additives in plastic to pesticides used on food crops. Growing evidence suggests that EDCs not only influence reproductive fitness and cancer incidence, but also immune fitness. For example, children exposed prenatally to a variety of EDCs had an increased incidence of infectious diseases and mounted a suboptimal vaccination response when challenged. Furthermore, women exposed in utero to diethylstilbestrol (a model estrogen known to cause reproductive cancers) showed an increase in autoimmune and infectious disease. Moreover, allergic diseases and asthma have increased in the past few decades, particularly in children. Because of the time frame, the rapid rise in immune disease cannot be attributed to genetics. The general consensus is that environmental exposures, particularly during fetal development, may be a significant factor in the development of immune disease. Though evidence is mounting that supports a negative role for EDC in immune system development, critical questions remain. At what stage and what doses are humans most vulnerable to the immune impacts of endocrine-disrupting chemicals? Studies have shown that the developing immune system (during gestation) is uniquely vulnerable and more vulnerable than the adult immune system. We hypothesize that diethylstilbestrol and methoxychlor (two established EDCs) alter T cell differentiation when present during prenatal immune system development, ultimately leading to inappropriate immune suppression or activation. Using an in vitro prenatal T cell differentiation assay, the experiments in this proposal will determine whether DES and MXC 1) are capable of altering the immune system during embryological development at low doses, 2) are mediating their effects through inhibition of development, or 3) are mediating their effects through induction of apoptosis. This stage-specific analysis of DES and MXC will enhance our understanding of how and when these endocrine disruptors affect the immune system, and will form the basis for assessment of prenatal immunotoxicity of other EDCs and for strategies to prevent immune disease induced by gestational EDC exposure. PUBLIC HEALTH RELEVANCE: Endocrine-disrupting chemicals (EDCs) are present throughout the environment, from wastewater releases (e.g. personal care products and pharmaceuticals) to additives in plastic (e.g. bisphenol A) to pesticides used on food crops (e.g. atrazine). Growing evidence suggests that EDCs negatively influence the immune system, potentially leading to immune diseases like asthma, allergies, autoimmune disease, repeated ear infections, and poor vaccine responses, particularly in children. The proposed research will enhance our understanding of how and when EDCs affect the immune system, and will form the basis for assessment of prenatal immune impacts of EDCs and for strategies to prevent immune disease caused by prenatal EDC exposure.